FLT3 signaling (Homo sapiens)

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141715, 23104, 2620, 232, 615, 20, 2313, 203215, 20, 2332, 19, 232, 5, 9, 16cytosolADPActive FLT3:HCKActiveFLT3:GRB2:p-Y-GAB2:PTPN11Autophosphorylated FLT3 PTPN11 ActiveFLT3:GRB2:GAB2S-Farn-Me KRAS4B FLT3LG dimer:FLT3dimerGAB2FLT3 FLT3LG dimerSTAT5 ActivationAutophosphorylated FLT3 p-Y-GAB2 p21 RAS:GTPFLT3LG S-Farn-Me-PalmS KRAS4A GRB2-1 Autophosphorylated FLT3 Autophosphorylated FLT3 p-Y-GAB2 p-Y-GAB2 GRB2-1Active FLT3:FYNSOS1 ActiveFLT3:GRB2:SOS1FLT3LG FLT3LG ATPGDP p21 RAS:GDPAutophosphorylated FLT3 FLT3ADPS-Farn-Me KRAS4B FYNSOS1S-Farn-Me PalmS NRAS FLT3LG FLT3LG GRB2-1 ATPActive FLT3: GRB2PTPN11 FYN FLT3LG S-Farn-Me-PalmS KRAS4A FLT3LG Autophosphorylated FLT3 GDPFLT3LG dimer:FLT3Autophosphorylated FLT3 ActiveFLT3:GRB2:p-Y-GAB2:PIK3R1FLT3LG FLT3LG PTPN11GTP FLT3LG GRB2-1 S-Farn-Me PalmS NRAS Active FLT3HCK PIK3R1ActiveFLT3:GRB2:p-Y-GAB2FLT3LG PIK3R1 Autophosphorylated FLT3 Autophosphorylated FLT3 GRB2-1 FLT3LG HCKGRB2-1 GAB2 RAF/MAP kinasecascadeAutophosphorylated FLT3 S-Farn-Me-2xPalmS HRAS FLT3 FLT3LG GTPS-Farn-Me-2xPalmS HRAS PI3K CascadeActive FLT3:PTPN11GRB2-1 1, 7, 8, 11, 12, 18...525


Description

Feline McDonough Sarcoma-like tyrosine kinase (FLT3) (also known as FLK2 (fetal liver tyrosine kinase 2), STK-1 (stem cell tyrosine kinase 1) or CD135) is a member of the class III receptor tyrosine kinase family involved in the differentiation, proliferation and survival of hematopoietic progenitor cells and of dendritic cells. Upon FLT3 ligand (FL) binding, the receptor forms dimers and is phosphorylated. Consequently, adapter and signaling molecules bind with the active receptor and trigger the activation of various pathways downstream including PI3K/Akt and MAPK cascades (Grafone T et al. 2012). View original pathway at Reactome.

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Pathway is converted from Reactome ID: 9607240
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Reactome version: 73

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Bibliography

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  103. Kazi JU, Rönnstrand L.; ''Suppressor of cytokine signaling 2 (SOCS2) associates with FLT3 and negatively regulates downstream signaling.''; PubMed Europe PMC Scholia
  104. Galanis A, Ma H, Rajkhowa T, Ramachandran A, Small D, Cortes J, Levis M.; ''Crenolanib is a potent inhibitor of FLT3 with activity against resistance-conferring point mutants.''; PubMed Europe PMC Scholia
  105. Kazi JU, Rönnstrand L.; ''Src-Like adaptor protein (SLAP) binds to the receptor tyrosine kinase Flt3 and modulates receptor stability and downstream signaling.''; PubMed Europe PMC Scholia
  106. Nabinger SC, Li XJ, Ramdas B, He Y, Zhang X, Zeng L, Richine B, Bowling JD, Fukuda S, Goenka S, Liu Z, Feng GS, Yu M, Sandusky GE, Boswell HS, Zhang ZY, Kapur R, Chan RJ.; ''The protein tyrosine phosphatase, Shp2, positively contributes to FLT3-ITD-induced hematopoietic progenitor hyperproliferation and malignant disease in vivo.''; PubMed Europe PMC Scholia
  107. Ray A, James MK, Larochelle S, Fisher RP, Blain SW.; ''p27Kip1 inhibits cyclin D-cyclin-dependent kinase 4 by two independent modes.''; PubMed Europe PMC Scholia
  108. Reiter A, Gotlib J.; ''Myeloid neoplasms with eosinophilia.''; PubMed Europe PMC Scholia
  109. Leischner H, Albers C, Grundler R, Razumovskaya E, Spiekermann K, Bohlander S, Rönnstrand L, Götze K, Peschel C, Duyster J.; ''SRC is a signaling mediator in FLT3-ITD- but not in FLT3-TKD-positive AML.''; PubMed Europe PMC Scholia
  110. Arrouchi H, Lakhlili W, Ibrahimi A.; ''A review on PIM kinases in tumors.''; PubMed Europe PMC Scholia
  111. Walz C, Erben P, Ritter M, Bloor A, Metzgeroth G, Telford N, Haferlach C, Haferlach T, Gesk S, Score J, Hofmann WK, Hochhaus A, Cross NC, Reiter A.; ''Response of ETV6-FLT3-positive myeloid/lymphoid neoplasm with eosinophilia to inhibitors of FMS-like tyrosine kinase 3.''; PubMed Europe PMC Scholia
  112. Cseh B, Doma E, Baccarini M.; ''"RAF" neighborhood: protein-protein interaction in the Raf/Mek/Erk pathway.''; PubMed Europe PMC Scholia
  113. Verstraete K, Vandriessche G, Januar M, Elegheert J, Shkumatov AV, Desfosses A, Van Craenenbroeck K, Svergun DI, Gutsche I, Vergauwen B, Savvides SN.; ''Structural insights into the extracellular assembly of the hematopoietic Flt3 signaling complex.''; PubMed Europe PMC Scholia
  114. Yee KW, O'Farrell AM, Smolich BD, Cherrington JM, McMahon G, Wait CL, McGreevey LS, Griffith DJ, Heinrich MC.; ''SU5416 and SU5614 inhibit kinase activity of wild-type and mutant FLT3 receptor tyrosine kinase.''; PubMed Europe PMC Scholia
  115. Hayakawa F, Towatari M, Kiyoi H, Tanimoto M, Kitamura T, Saito H, Naoe T.; ''Tandem-duplicated Flt3 constitutively activates STAT5 and MAP kinase and introduces autonomous cell growth in IL-3-dependent cell lines.''; PubMed Europe PMC Scholia
  116. Kyriakis JM, Avruch J.; ''Mammalian MAPK signal transduction pathways activated by stress and inflammation: a 10-year update.''; PubMed Europe PMC Scholia
  117. Chougule RA, Kazi JU, Rönnstrand L.; ''FYN expression potentiates FLT3-ITD induced STAT5 signaling in acute myeloid leukemia.''; PubMed Europe PMC Scholia
  118. Zheng R, Levis M, Piloto O, Brown P, Baldwin BR, Gorin NC, Beran M, Zhu Z, Ludwig D, Hicklin D, Witte L, Li Y, Small D.; ''FLT3 ligand causes autocrine signaling in acute myeloid leukemia cells.''; PubMed Europe PMC Scholia
  119. Larrosa-Garcia M, Baer MR.; ''FLT3 Inhibitors in Acute Myeloid Leukemia: Current Status and Future Directions.''; PubMed Europe PMC Scholia
  120. Bertoli S, Boutzen H, David L, Larrue C, Vergez F, Fernandez-Vidal A, Yuan L, Hospital MA, Tamburini J, Demur C, Delabesse E, Saland E, Sarry JE, Galcera MO, Mansat-De Mas V, Didier C, Dozier C, Récher C, Manenti S.; ''CDC25A governs proliferation and differentiation of FLT3-ITD acute myeloid leukemia.''; PubMed Europe PMC Scholia
  121. Godfrey R, Arora D, Bauer R, Stopp S, Müller JP, Heinrich T, Böhmer SA, Dagnell M, Schnetzke U, Scholl S, Östman A, Böhmer FD.; ''Cell transformation by FLT3 ITD in acute myeloid leukemia involves oxidative inactivation of the tumor suppressor protein-tyrosine phosphatase DEP-1/ PTPRJ.''; PubMed Europe PMC Scholia

History

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CompareRevisionActionTimeUserComment
129740view01:54, 22 May 2024EweitzModified title
115094view17:04, 25 January 2021ReactomeTeamReactome version 75
113536view12:01, 2 November 2020ReactomeTeamReactome version 74
112837view18:43, 9 October 2020DeSlOntology Term : 'kinase mediated signaling pathway' added !
112782view16:18, 9 October 2020ReactomeTeamNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
ADPMetaboliteCHEBI:456216 (ChEBI)
ATPMetaboliteCHEBI:30616 (ChEBI)
Active FLT3:GRB2:GAB2ComplexR-HSA-9606619 (Reactome)
Active FLT3:GRB2:SOS1ComplexR-HSA-9607300 (Reactome)
Active FLT3:GRB2:p-Y-GAB2:PIK3R1ComplexR-HSA-9607223 (Reactome)
Active FLT3:GRB2:p-Y-GAB2:PTPN11ComplexR-HSA-9606788 (Reactome)
Active FLT3:GRB2:p-Y-GAB2ComplexR-HSA-9606627 (Reactome)
Active FLT3: GRB2ComplexR-HSA-9604756 (Reactome)
Active FLT3:FYNComplexR-HSA-9605257 (Reactome)
Active FLT3:HCKComplexR-HSA-9609280 (Reactome)
Active FLT3:PTPN11ComplexR-HSA-9604972 (Reactome)
Active FLT3ComplexR-HSA-9604751 (Reactome)
Autophosphorylated FLT3 ProteinP36888 (Uniprot-TrEMBL)
FLT3 ProteinP36888 (Uniprot-TrEMBL)
FLT3LG ProteinP49771 (Uniprot-TrEMBL)
FLT3LG dimer:FLT3 dimerComplexR-HSA-8854716 (Reactome)
FLT3LG dimer:FLT3ComplexR-HSA-6786754 (Reactome)
FLT3LG dimerComplexR-HSA-8854740 (Reactome)
FLT3ProteinP36888 (Uniprot-TrEMBL)
FYN ProteinP06241 (Uniprot-TrEMBL)
FYNProteinP06241 (Uniprot-TrEMBL)
GAB2 ProteinQ9UQC2 (Uniprot-TrEMBL)
GAB2ProteinQ9UQC2 (Uniprot-TrEMBL)
GDP MetaboliteCHEBI:17552 (ChEBI)
GDPMetaboliteCHEBI:17552 (ChEBI)
GRB2-1 ProteinP62993-1 (Uniprot-TrEMBL)
GRB2-1ProteinP62993-1 (Uniprot-TrEMBL)
GTP MetaboliteCHEBI:15996 (ChEBI)
GTPMetaboliteCHEBI:15996 (ChEBI)
HCK ProteinP08631 (Uniprot-TrEMBL)
HCKProteinP08631 (Uniprot-TrEMBL)
PI3K CascadePathwayR-HSA-109704 (Reactome) The PI3K (Phosphatidlyinositol-3-kinase) - AKT signaling pathway stimulates cell growth and survival.
PIK3R1 ProteinP27986 (Uniprot-TrEMBL)
PIK3R1ProteinP27986 (Uniprot-TrEMBL)
PTPN11 ProteinQ06124 (Uniprot-TrEMBL)
PTPN11ProteinQ06124 (Uniprot-TrEMBL)
RAF/MAP kinase cascadePathwayR-HSA-5673001 (Reactome) The RAS-RAF-MEK-ERK pathway regulates processes such as proliferation, differentiation, survival, senescence and cell motility in response to growth factors, hormones and cytokines, among others. Binding of these stimuli to receptors in the plasma membrane promotes the GEF-mediated activation of RAS at the plasma membrane and initiates the three-tiered kinase cascade of the conventional MAPK cascades. GTP-bound RAS recruits RAF (the MAPK kinase kinase), and promotes its dimerization and activation (reviewed in Cseh et al, 2014; Roskoski, 2010; McKay and Morrison, 2007; Wellbrock et al, 2004). Activated RAF phosphorylates the MAPK kinase proteins MEK1 and MEK2 (also known as MAP2K1 and MAP2K2), which in turn phophorylate the proline-directed kinases ERK1 and 2 (also known as MAPK3 and MAPK1) (reviewed in Roskoski, 2012a, b; Kryiakis and Avruch, 2012). Activated ERK proteins may undergo dimerization and have identified targets in both the nucleus and the cytosol; consistent with this, a proportion of activated ERK protein relocalizes to the nucleus in response to stimuli (reviewed in Roskoski 2012b; Turjanski et al, 2007; Plotnikov et al, 2010; Cargnello et al, 2011). Although initially seen as a linear cascade originating at the plasma membrane and culminating in the nucleus, the RAS/RAF MAPK cascade is now also known to be activated from various intracellular location. Temporal and spatial specificity of the cascade is achieved in part through the interaction of pathway components with numerous scaffolding proteins (reviewed in McKay and Morrison, 2007; Brown and Sacks, 2009).
The importance of the RAS/RAF MAPK cascade is highlighted by the fact that components of this pathway are mutated with high frequency in a large number of human cancers. Activating mutations in RAS are found in approximately one third of human cancers, while ~8% of tumors express an activated form of BRAF (Roberts and Der, 2007; Davies et al, 2002; Cantwell-Dorris et al, 2011).
S-Farn-Me KRAS4B ProteinP01116-2 (Uniprot-TrEMBL)
S-Farn-Me PalmS NRAS ProteinP01111 (Uniprot-TrEMBL)
S-Farn-Me-2xPalmS HRAS ProteinP01112 (Uniprot-TrEMBL)
S-Farn-Me-PalmS KRAS4A ProteinP01116-1 (Uniprot-TrEMBL)
SOS1 ProteinQ07889 (Uniprot-TrEMBL)
SOS1ProteinQ07889 (Uniprot-TrEMBL)
STAT5 ActivationPathwayR-HSA-9645135 (Reactome) Signal transducer and activator of transcription (STAT) constitutes a family of universal transcription factors. STAT5 refers to two highly related proteins, STAT5A and STAT5B, with critical function in cell survival and proliferation. Several upstream signals including cytokines and growth factors can trigger STAT5 activation.
p-Y-GAB2 ProteinQ9UQC2 (Uniprot-TrEMBL)
p21 RAS:GDPComplexR-HSA-109796 (Reactome)
p21 RAS:GTPComplexR-HSA-109783 (Reactome)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
ADPArrowR-HSA-9604767 (Reactome)
ADPArrowR-HSA-9606622 (Reactome)
ATPR-HSA-9604767 (Reactome)
ATPR-HSA-9606622 (Reactome)
Active FLT3:GRB2:GAB2ArrowR-HSA-9606624 (Reactome)
Active FLT3:GRB2:GAB2R-HSA-9606622 (Reactome)
Active FLT3:GRB2:SOS1ArrowR-HSA-9607301 (Reactome)
Active FLT3:GRB2:SOS1mim-catalysisR-HSA-9607304 (Reactome)
Active FLT3:GRB2:p-Y-GAB2:PIK3R1ArrowR-HSA-9607224 (Reactome)
Active FLT3:GRB2:p-Y-GAB2:PTPN11ArrowR-HSA-9606784 (Reactome)
Active FLT3:GRB2:p-Y-GAB2ArrowR-HSA-9606622 (Reactome)
Active FLT3:GRB2:p-Y-GAB2R-HSA-9606784 (Reactome)
Active FLT3:GRB2:p-Y-GAB2R-HSA-9607224 (Reactome)
Active FLT3: GRB2ArrowR-HSA-9604738 (Reactome)
Active FLT3: GRB2R-HSA-9606624 (Reactome)
Active FLT3: GRB2R-HSA-9607301 (Reactome)
Active FLT3:FYNArrowR-HSA-9605259 (Reactome)
Active FLT3:HCKArrowR-HSA-9609274 (Reactome)
Active FLT3:PTPN11ArrowR-HSA-9604969 (Reactome)
Active FLT3ArrowR-HSA-9604767 (Reactome)
Active FLT3R-HSA-9604738 (Reactome)
Active FLT3R-HSA-9604969 (Reactome)
Active FLT3R-HSA-9605259 (Reactome)
Active FLT3R-HSA-9609274 (Reactome)
FLT3LG dimer:FLT3 dimerArrowR-HSA-8854736 (Reactome)
FLT3LG dimer:FLT3 dimerR-HSA-9604767 (Reactome)
FLT3LG dimer:FLT3 dimermim-catalysisR-HSA-9604767 (Reactome)
FLT3LG dimer:FLT3ArrowR-HSA-6786789 (Reactome)
FLT3LG dimer:FLT3R-HSA-8854736 (Reactome)
FLT3LG dimerR-HSA-6786789 (Reactome)
FLT3R-HSA-6786789 (Reactome)
FLT3R-HSA-8854736 (Reactome)
FYNR-HSA-9605259 (Reactome)
GAB2R-HSA-9606624 (Reactome)
GDPArrowR-HSA-9607304 (Reactome)
GRB2-1R-HSA-9604738 (Reactome)
GTPR-HSA-9607304 (Reactome)
HCKR-HSA-9609274 (Reactome)
PIK3R1R-HSA-9607224 (Reactome)
PTPN11R-HSA-9604969 (Reactome)
PTPN11R-HSA-9606784 (Reactome)
R-HSA-6786789 (Reactome) FLT3 is a member of the Class III Receptor Tyrosine Kinase Family, which also includes FMS, KIT, PDGFRA and PDGFRB. It binds the cytokine FLT3LG (Hannum et al. 1994), which regulates differentiation, proliferation and survival of hematopoietic progenitor cells and dendritic cells.

FLT3LG is probably dimeric. Binding to monomeric FLT3 induces receptor dimerization (Verstraete et al. 2011, Grafone et al. 2012), which promotes phosphorylation of the tyrosine kinase domain, activating the receptor and consequently the downstream effectors. Early studies of FLT3 using a chimeric receptor composed of the extracellular domain of human FMS and the transmembrane and cytoplasmic domains of FLT3 demonstrated the activation of PLCG1, RASA1, SHC, GRB2, VAV, FYN, and SRC pathways. PLCG1, SHC, GRB2, and FYN were found to directly associate with the cytoplasmic domain of FLT3 (Dosil et al. 1993). Later studes using the full-length human receptor identified that FLT3LG binding to FLT3 leads to FLT3 autophosphorylation, association of FLT3 with GRB2, tyrosine phosphorylation of SHC and CBL, formation of a complex that includes CBL, the p85 subunit of PI3K and GAB2, and tyrosine phosphorylation of GAB1 and GAB2 and their association with PTPN11 (SHP-2) and GRB2. PTPN11 (SHP-2), but not PTPN6 (SHP-1) binds GRB2 directly and becomes tyrosine-phosphorylated in response to FLT3LG stimulation. INPP5D (SHIP) also becomes tyrosine-phosphorylated after FLT3LG stimulation but binds to SHC. GAB1 and GAB2 are rapidly tyrosine phosphorylated after FLT3LG stimulation of cells, interacting with tyrosine-phosphorylated PTPN11, p85 subunit of PI3K, GRB2, and SHC (Zhang & Broxmeyer 2000). GAB may mediate the downstream activation of PTPN11, PI3K and thereby PDK1 and AKt which activate the mTOR pathway (Grafone et al. 2012), and possibly the Ras/Raf/MAPK pathway. (Zhang et al. 1999, Marchetto et al. 1999, Zhang e& Broxmeyer 2000). Activation of FLT3 leads to limited activation of STAT5A via a JAK-independent mechanism (Zhang et al. 2000).

FLT3 is mutated in about 1/3 of acute myeloid leukemia (AML) patients, either by internal tandem duplications (ITD) of the juxtamembrane domain or by point mutations usually involving the kinase domain (KD). Both types of mutation constitutively activate FLT3 (Small 2006).
R-HSA-8854736 (Reactome) Binding of FLT3LG to monomeric FLT3 induces receptor dimerization (Verstraete et al. 2011, Grafone et al. 2012).
R-HSA-9604738 (Reactome) Feline McDonough Sarcoma-like tyrosine kinase (FLT3) is a member of the class III tyrosine kinase receptor family. Ligand binding induces conformational changes in the FLT3 receptor, which facilitates its dimerization and autophosphorylation. Once fully active, FLT3 receptors can associate with growth factor receptor-bound protein 2 (GRB2) and facilitate downstream regulation of effectors (Masson et al. 2009, Chonabayashi et al. 2013). Experiments confirming this event were performed in mouse cells.
R-HSA-9604767 (Reactome) Feline McDonough Sarcoma-like tyrosine kinase (FLT3) is a member of the class III tyrosine kinase receptor family. Ligand binding induces conformational changes in FLT3 receptor, which facilitates its dimerization. This process exposes phosphate acceptor sites in the catalytic domain of FLT3. Subsequently, FLT3 autophosphorylates at these sites. Several phosphorylation sites have been reported and there may be more modifications required to fully activate FLT3 (Heiss et al. 2006, Masson et al. 2009, Razumovskaya et al. 2009). Experiments confirming this event were performed in mouse cells.
R-HSA-9604969 (Reactome) Feline McDonough Sarcoma-like tyrosine kinase (FLT3) is a member of the class III tyrosine kinase receptor family. Ligand binding induces conformational changes in the FLT3 receptor, which facilitates its dimerization and autophosphorylation. Once fully active, tyrosine-protein phosphatase non-receptor type 11 (PTPN11) has been reported to directly bind to the Y599 site of Flt3 receptors thereby facilitating downstream regulation of effectors (Heiss et al. 2006, Nabinger et al. 2013). Experiments confirming this event were performed in mouse cells. Interaction of FLT3 with PTPN11 is known to trigger STAT5 activation in various pathological conditions (Mizuki M et al. 2000, Rocnik JL et al. 2006).
R-HSA-9605259 (Reactome) Feline McDonough Sarcoma-like tyrosine kinase (FLT3) is a member of the class III tyrosine kinase receptor family. Ligand binding induces conformational changes in the FLT3 receptor, which facilitates its dimerization and autophosphorylation. Subsequently, tyrosine-protein kinase Fyn (FYN) associates with the phosphorylated residues of fully active FLT3 (Y591, Y599 and pY955) through its SH2 domain (Dosil et al. 1993, Chougule et al. 2016). Experiments confirming this event were performed in mouse cells.
R-HSA-9606622 (Reactome) Feline McDonough Sarcoma-like tyrosine kinase (FLT3) is a member of the class III tyrosine kinase receptor family. Ligand binding induces conformational changes in the FLT3 receptor, which facilitates its dimerization and autophosphorylation. Once fully active, FLT3 receptors can associate with growth factor receptor-bound protein 2 (GRB2), which then recruits GRB2-associated-binding protein 2 (GAB2). Consequently, GAB2 is phosphorylated (Zhang et al. 2000, Masson et al. 2009, Chonabayashi et al. 2013). The precise phosphorylation mechanism of GAB2 is unclear. Experiments confirming this event were performed in mouse cells.
R-HSA-9606624 (Reactome) Feline McDonough Sarcoma-like tyrosine kinase (FLT3) is a member of the class III tyrosine kinase receptor family. Ligand binding induces conformational changes in the FLT3 receptor, which facilitates its dimerization and autophosphorylation. Once fully active, FLT3 receptors can associate with growth factor receptor-bound protein 2 (GRB2). Subsequently, GRB2-associated-binding protein 2 (GAB2) binds GRB2 (Zhang et al. 2000, Masson et al. 2009, Chonabayashi et al. 2013). Experiments confirming this event were performed in mouse cells.
R-HSA-9606784 (Reactome) Feline McDonough Sarcoma-like tyrosine kinase (FLT3) is a member of the class III tyrosine kinase receptor family. Ligand binding induces conformational changes in the FLT3 receptor, which facilitates its dimerization and autophosphorylation. Once fully active, FLT3 receptors can associate with growth factor receptor-bound protein 2 (GRB2), which then recruits GRB2-associated-binding protein 2 (GAB2). Consequently, GAB2 is phosphorylated and recruits tyrosine-protein phosphatase non-receptor type 11 (PTPN11). The serine residue at position 623 in GAB2 is known to be involved in PTPN11 binding (Zhang et al. 2000, Arnaud et al. 2004). The precise association mechanism of GAB2 and PTPN11 is unclear. Experiments confirming this event were performed in mouse cells. Interaction of FLT3 with PTPN11 is known to trigger STAT5 activation in various pathological conditions.
R-HSA-9607224 (Reactome) Feline McDonough Sarcoma-like tyrosine kinase (FLT3) is a member of the class III tyrosine kinase receptor family. Ligand binding induces conformational changes in the FLT3 receptor, which facilitates its dimerization and autophosphorylation. Once fully active, FLT3 receptors can associate with growth factor receptor-bound protein 2 (GRB2), which then recruits GRB2-associated-binding protein 2 (GAB2). Consequently, GAB2 is phosphorylated and recruits phosphatidylinositol 3-kinase regulatory subunit alpha (PIK3R1). The p85 alpha subunit of PIK3R1 is known to bind with GAB2. Ultimately, the PI3K/Akt pathway is activated (Zhang et al. 2000, Masson et al. 2009). Experiments confirming this event were performed in mouse cells.
R-HSA-9607301 (Reactome) Feline McDonough Sarcoma-like tyrosine kinase (FLT3) is a member of the class III tyrosine kinase receptor family. Ligand binding induces conformational changes in the FLT3 receptor, which facilitates its dimerization and autophosphorylation. Once fully active, FLT3 receptors can associate with growth factor receptor-bound protein 2 (GRB2), which then recruits Son of sevenless homolog 1 (SOS1). Consequently, this triggers the activation of the ERK signaling cascade (Li et al. 1993).
R-HSA-9607304 (Reactome) Son of sevenless homolog 1 (SOS1) is the guanine nucleotide exchange factor (GEF) for rat sarcoma (RAS) protein. SOS1 activates RAS nucleotide exchange from the inactive form (bound to GDP) to an active form (bound to GTP).
R-HSA-9609274 (Reactome) Feline McDonough Sarcoma-like tyrosine kinase (FLT3) is a member of the class III tyrosine kinase receptor family. Ligand binding induces conformational changes in the FLT3 receptor, which facilitates its dimerization and autophosphorylation. Tyrosine-protein kinase HCK (HCK) associates with the phosphorylated Y589 and Y591 residues of FLT3. This binding results in further phosphorylation of the FLT3 receptor to make it fully active (Heiss et al. 2006, Mitina et al. 2007). There may be more unknown binding sites for HCK on FLT3.
SOS1R-HSA-9607301 (Reactome)
p21 RAS:GDPR-HSA-9607304 (Reactome)
p21 RAS:GTPArrowR-HSA-9607304 (Reactome)
Retrieved from "https://classic.wikipathways.org/index.php/Pathway:WP5016"
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